Braak Neurofibrillary Tangle Research Articles

Primary progressive apraxia of speech: Clinico-pathological associations of left-right hemispheric dominance (S8.008)

<h3>Objective:</h3> To determine whether there are differences in in demographics, clinicopathologic-neuroimaging or survival, between left-dominant, right-dominant, and symmetric PPAOS. <h3>Background:</h3> Primary progressive apraxia of speech (PPAOS) is a neurodegenerative syndrome associated with neuroimaging abnormalities affecting the lateral premotor cortex (LPC) and supplementary motor area (SMA). It is unclear whether relative greater damage to premotor regions in left/right hemisphere is associated with differences in baseline and/or longitudinal features. <h3>Design/Methods:</h3> Fifty-one prospectively recruited PPAOS patients who completed [¹⁸F]-fluorodeoxyglucose PET scanning were classified as left-dominant, right-dominant, or symmetric, based on visual assessment of the LPC and SMA on FDG-PET by independent raters. Statistical analyses were utilized to compared baseline and longitudinal features. Kaplan-Meyer curves and Cox proportional hazards were used to evaluate survival differences across groups. <h3>Results:</h3> 49% of PPAOS patients were identified as left-dominant, 31% as right-dominant, and 20% as symmetric. At baseline, there were no differences between groups. On longitudinal rates of clinical change, left-dominant PPAOS displayed a slower progression of Parkinsonian symptoms on the Unified Parkinson Disease Rating Scale-III (p=0.047), with a trend for slowest rates of progression in ideomotor apraxia (p=0.06) and motor speech severity (p=0.09) relative to other groups. Right-dominant PPAOS demonstrated the most rapid rates of progression of behavioral disturbances on the Frontal Behavioral Inventory (p=0.02), including disinhibition symptoms (p=0.02) and negative behaviors (p=0.05). The symmetric group had fastest worsening of dysarthria. There were no differences in survival, although a five-year increase in age at onset, but not group classification, was associated with shorter survival (Hazard Ratio = 1.32; p=0.007). Braak neurofibrillary tangle stage differed across groups (p=0.01). While not statistically significant, right-dominant PPAOS tended to have corticobasal degeneration (CBD) and left-dominant PPAOS had progressive supranuclear palsy (PSP) pathology at autopsy. <h3>Conclusions:</h3> Patients with PPAOS and a left-dominant pattern of hypometabolism on FDG-PET have the slowest rate of decline of clinical features. <b>Disclosure:</b> Miss Robinson has nothing to disclose. The institution of Joseph Duffy has received research support from NIH. Joseph Duffy has received publishing royalties from a publication relating to health care. Heather Clark has received personal compensation for serving as an employee of Mayo Clinic. The institution of Heather Clark has received research support from NIH. Heather Clark has received publishing royalties from a publication relating to health care. The institution of Rene Utianski has received research support from NIH. The institution of Dr. Machulda has received research support from NIH. Dr. Botha has received research support from NIH. Dr. Singh has nothing to disclose. Nha Trang Thu Pham has received personal compensation for serving as an employee of Mayo Clinic. Mr. Martin has nothing to disclose. The institution of Dr. Taner has received research support from NIH. Dr. Dickson has nothing to disclose. Dr. Lowe has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for AVID Radiopharmaceutical. Dr. Lowe has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai Inc. The institution of Dr. Lowe has received research support from AVID Radiopharmaceuticals. Dr. Whitwell has nothing to disclose. Dr. Josephs has nothing to disclose.

Effect of APOE ɛ4 genotype on age at onset and comorbid pathologies in multiple system atrophy (P8-11.004)

<h3>Objective:</h3> To elucidate the effect of apolipoprotein (APOE) ɛ4 genotype on age at onset and comorbid pathologies in multiple system atrophy (MSA). <h3>Background:</h3> APOE ɛ4 increases risk of Alzheimer’s disease (AD) and lowers age of onset of late-onset AD. In synucleinopathy, APOE ɛ4 has been reported to correlate with the severity of Lewy body pathology in Lewy body disease and to lower the age of onset of Parkinson’s disease. The association of APOE E4 with MSA is not well understood. <h3>Design/Methods:</h3> This study included 145 pathologically confirmed MSA patients (female 43%) in the Mayo Clinic Brain Bank. We reviewed the medical records to identify the age at onset at which motor or autonomic symptoms presented. MSA patients were divided into two groups: APOE ɛ4 carriers and non-carriers. We examined comorbid pathologies, including AD pathology, Lewy-related pathology, TDP-43 proteinopathy, argyrophilic grains, cerebral amyloid angiopathy (CAA), and aging-related tau astrogliopathy (ARTAG). We defined the presence of AD pathology based on the Braak neurofibrillary tangle stage and the Thal amyloid phase if both were equal or greater than 3. We compared the frequency of each pathology between APOE ɛ4 carriers and non-carriers. <h3>Results:</h3> Among 145 MSA patients, 26% (37/145) had APOE ɛ4 (female 41%) and 74% (108/145) had non-ɛ4 (female 44%). Age at onset was significantly younger in MSA with APOE ɛ4 than non-ɛ4 (P = 0.028, 56 ± 6 vs. 60 ± 10 years old). The frequency of CAA was significantly greater in MSA with APOE ɛ4 than non-ɛ4 (P = 0.0032, 43% vs. 18%); however, there was no significant difference in the frequency of AD pathology, Lewy-related pathology, TDP-43 proteinopathy, argyrophilic grains, and ARTAG. <h3>Conclusions:</h3> Our results indicate that APOE ɛ4 is associated with CAA in MSA, as well as lower age at onset, but not AD or Lewy-related pathologies. <b>Disclosure:</b> Dr. Sekiya has nothing to disclose. Dr. Koga has nothing to disclose. Dr. Ross has nothing to disclose. Dr. Dickson has nothing to disclose.

The correlation between neuropathology levels and cognitive performance in centenarians.

Neuropathological substrates associated with neurodegeneration occur in brains of the oldest old. How does this affect cognitive performance? The 100-plus Study is an ongoing longitudinal cohort study of centenarians who self-report to be cognitively healthy; post mortem brain donation is optional. In 85 centenarian brains, we explored the correlations between the levels of 11 neuropathological substrates with ante mortem performance on 12 neuropsychological tests. Levels of neuropathological substrates varied: we observed levels up to Thal-amyloid beta phase 5, Braak-neurofibrillary tangle (NFT) stage V, Consortium to Establish a Registry for Alzheimer's Disease (CERAD)-neuritic plaque score 3, Thal-cerebral amyloid angiopathy stage 3, Tar-DNA binding protein 43 (TDP-43) stage 3, hippocampal sclerosis stage 1, Braak-Lewy bodies stage 6, atherosclerosis stage 3, cerebral infarcts stage 1, and cerebral atrophy stage 2. Granulovacuolar degeneration occurred in all centenarians. Some high performers had the highest neuropathology scores. Only Braak-NFT stage and limbic-predominant age-related TDP-43 encephalopathy (LATE) pathology associated significantly with performance across multiple cognitive domains. Of all cognitive tests, the clock-drawing test was particularly sensitive to levels of multiple neuropathologies.

Clinicopathological associations of hemispheric dominance in primary progressive apraxia of speech.

Primary progressive apraxia of speech (PPAOS) is associated with imaging abnormalities in the lateral premotor cortex (LPC) and supplementary motor area (SMA). It is not known whether greater involvement of these regions in either hemisphere is associated with demographics, presenting, and/or longitudinal features. In 51 prospectively recruited PPAOS patients who completed [18 F]-fluorodeoxyglucose (FDG) positron emission tomography (PET), we classified patients as left-dominant, right-dominant, or symmetric, based on visual assessment of the LPC and SMA on FDG-PET. SPM and statistical analyses of regional metabolic values were performed. Diagnosis of PPAOS was made if apraxia of speech was present and aphasia absent. Thirteen patients completed ioflupane-123I (dopamine transporter [DAT]) scans. We compared cross-sectional and longitudinal clinicopathological, genetic, and neuroimaging characteristics across the three groups, with area under the receiver-operating curve (AUROC) determined as a measure of effect size. In all, 49% of the PPAOS patients were classified as left-dominant, 31% as right-dominant, and 20% as symmetric, which was supported by results from the SPM and regional analyses. There were no differences in baseline characteristics. Longitudinally, right-dominant PPAOS showed faster rates of progression of ideomotor apraxia (AUROC0.79), behavioral disturbances (AUROC 0.84), including disinhibition symptoms (AUROC0.82) and negative behaviors (AUROC 0.82), and parkinsonism (AUROC 0.75) compared to left-dominant PPAOS. Symmetric PPAOS showed faster rates of dysarthria progression compared to left-dominant (AUROC 0.89) and right-dominant PPAOS (AUROC 0.79). Five patients showed abnormal DAT uptake. Braak neurofibrillary tangle stage differed across groups (p=0.01). Patients with PPAOS and a right-dominant pattern of hypometabolism on FDG-PET have the fastest rates of decline of behavioral and motor features.

Assessment of Alzheimer-related pathologies of dementia using machine learning feature selection

Although a variety of brain lesions may contribute to the pathological assessment of dementia, the relationship of these lesions to dementia, how they interact and how to quantify them remains uncertain. Systematically assessing neuropathological measures by their degree of association with dementia may lead to better diagnostic systems and treatment targets. This study aims to apply machine learning approaches to feature selection in order to identify critical features of Alzheimer-related pathologies associated with dementia. We applied machine learning techniques for feature ranking and classification to objectively compare neuropathological features and their relationship to dementia status during life using a cohort (n=186) from the Cognitive Function and Ageing Study (CFAS). We first tested Alzheimer’s Disease and tau markers and then other neuropathologies associated with dementia. Seven feature ranking methods using different information criteria consistently ranked 22 out of the 34 neuropathology features for importance to dementia classification. Although highly correlated, Braak neurofibrillary tangle stage, beta-amyloid and cerebral amyloid angiopathy features were ranked the highest. The best-performing dementia classifier using the top eight neuropathological features achieved 79% sensitivity, 69% specificity and 75% precision. However, when assessing all seven classifiers and the 22 ranked features, a substantial proportion (40.4%) of dementia cases was consistently misclassified. These results highlight the benefits of using machine learning to identify critical indices of plaque, tangle and cerebral amyloid angiopathy burdens that may be useful for classifying dementia.

The prevalence, correlation, and co-occurrence of neuropathology in old age: harmonisation of 12 measures across six community-based autopsy studies of dementia

Population-based autopsy studies provide valuable insights into the causes of dementia but are limited by sample size and restriction to specific populations. Harmonisation across studies increases statistical power and allows meaningful comparisons between studies. We aimed to harmonise neuropathology measures across studies and assess the prevalence, correlation, and co-occurrence of neuropathologies in the ageing population. We combined data from six community-based autopsy cohorts in the US and the UK in a coordinated cross-sectional analysis. Among all decedents aged 80 years or older, we assessed 12 neuropathologies known to be associated with dementia: arteriolosclerosis, atherosclerosis, macroinfarcts, microinfarcts, lacunes, cerebral amyloid angiopathy, Braak neurofibrillary tangle stage, Consortium to Establish a Registry for Alzheimer's disease (CERAD) diffuse plaque score, CERAD neuritic plaque score, hippocampal sclerosis, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and Lewy body pathology. We divided measures into three groups describing level of confidence (low, moderate, and high) in harmonisation. We described the prevalence, correlations, and co-occurrence of neuropathologies. The cohorts included 4354 decedents aged 80 years or older with autopsy data. All cohorts included more women than men, with the exception of one study that only included men, and all cohorts included decedents at older ages (range of mean age at death across cohorts 88·0-91·6 years). Measures of Alzheimer's disease neuropathological change, Braak stage and CERAD scores, were in the high confidence category, whereas measures of vascular neuropathologies were in the low (arterioloscerosis, atherosclerosis, cerebral amyloid angiopathy, and lacunes) or moderate (macroinfarcts and microinfarcts) categories. Neuropathology prevalence and co-occurrence was high (2443 [91%] of 2695 participants had more than one of six key neuropathologies and 1106 [41%] of 2695 had three or more). Co-occurrence was strongly but not deterministically associated with dementia status. Vascular and Alzheimer's disease features clustered separately in correlation analyses, and LATE-NC had moderate associations with Alzheimer's disease measures (eg, Braak stage ρ=0·31 [95% CI 0·20-0·42]). Higher variability and more inconsistency in the measurement of vascular neuropathologies compared with the measurement of Alzheimer's disease neuropathological change suggests the development of new frameworks for the measurement of vascular neuropathologies might be helpful. Results highlight the complexity and multi-morbidity of the brain pathologies that underlie dementia in older adults and suggest that prevention efforts and treatments should be multifaceted. Gates Ventures.

Neuropathology-Independent Association Between APOE Genotype and Cognitive Decline Rate in the Normal Aging-Early Alzheimer Continuum.

We previously found that the APOE genotype affects the rate of cognitive decline in mild-to-moderate Alzheimer disease (AD) dementia independently of its effects on AD neuropathologic changes (ADNC) and copathologies. In this study, we tested the hypothesis that the APOE alleles differentially affect the rate of cognitive decline at the normal aging-early AD continuum and that this association is independent of their effects on classical ADNC and copathologies. We analyzed APOE associations with the cognitive trajectories (Clinical Dementia Rating scale Sum of Boxes [CDR-SOB] and Mini-Mental State Examination [MMSE]) of more than 1,000 individuals from a national clinicopathologic sample who had either no, mild (sparse neuritic plaques and the Braak neurofibrillary tangle [NFT] stage I/II), or intermediate (moderate neuritic plaques and the Braak NFT stage III/IV) ADNC levels at autopsy via 2 latent classes reverse-time longitudinal modeling. Carrying the APOEε4 allele was associated with a faster rate of cognitive decline by both CDR-SOB and MMSE relative to APOEε3 homozygotes. This association remained statistically significant after adjusting for ADNC severity, comorbid pathologies, and the effects of ADNC on the slope of cognitive decline. Our modeling strategy identified 2 latent classes in which APOEε4 carriers declined faster than APOEε3 homozygotes, with latent class 1 members representing slow decliners (CDR-SOB: 76.7% of individuals, 0.195 vs 0.146 points/y in APOEε4 vs APOEε3/ε3; MMSE: 88.6% of individuals, -0.303 vs -0.153 points/y in APOEε4 vs APOEε3/ε3), whereas latent class 2 members were fast decliners (CDR-SOB: 23.3% of participants, 1.536 vs 1.487 points/y in APOEε4 vs APOEε3/ε3; MMSE: 11.4% of participants, -2.538 vs -2.387 points/y in APOEε4 vs APOEε3/ε3). Compared with slow decliners, fast decliners were more likely to carry the APOEε4 allele, younger at initial visit and death, more impaired at initial and last visits, and more likely to have intermediate (vs none or mild) ADNC levels, as well as concurrent Lewy bodies and hippocampal sclerosis at autopsy. In a large national sample selected to represent the normal aging-early AD continuum, the APOEε4 allele is associated with a modest but statistically significant acceleration of the cognitive decline rate even after controlling for its effects on ADNC and comorbid pathologies.

Resilience and resistance to the accumulation of amyloid plaques and neurofibrillary tangles in centenarians: An age-continuous perspective.

With increasing age, neuropathological substrates associated with Alzheimer's disease (AD) accumulate in brains of cognitively healthy individuals-are they resilient, or resistant to AD-associated neuropathologies? In 85 centenarian brains, we correlated NIA (amyloid) stages, Braak (neurofibrillary tangle) stages, and CERAD (neuritic plaque) scores with cognitive performance close to death as determined by Mini-Mental State Examination (MMSE) scores. We assessed centenarian brains against 2131 brains from AD patients, non-AD demented, and non-demented individuals in an age continuum ranging from 16 to 100+ years. With age, brains from non-demented individuals reached the NIA and Braak stages observed in AD patients, while CERAD scores remained lower. In centenarians, NIA stages varied (22.4% were the highest stage 3), Braak stages rarely exceeded stage IV (5.9% were V), and CERAD scores rarely exceeded 2 (4.7% were 3); within these distributions, we observed no correlation with the MMSE (NIA: P=0.60; Braak: P=0.08; CERAD: P=0.16). Cognitive health can be maintained despite the accumulation of high levels of AD-related neuropathological substrates. Cognitively healthy elderly have AD neuropathology levels similar to AD patients. AD neuropathology loads do not correlate with cognitive performance in centenarians. Some centenarians are resilient to the highest levels of AD neuropathology.

Neuropathology in the LifeAfter90 Study: Update on an Ethnically Diverse Cohort Study of Oldest‐Old

AbstractBackgroundNeuropathology studies of the oldest‐old have significantly advanced our understanding of the multiple etiologies late in very late life; however, this has been limited to studies of oldest‐old non‐Hispanic white (NHW) decedents. Our goal was to characterize neuropathology in a cohort of diverse oldest‐old decedents.MethodThe Life after 90 study is an ongoing cohort study of members of Kaiser Permanente Northern California, aged 90+ with targeted recruitment of individuals across different racial/ethnic groups with no prior diagnosis of dementia in their medical record. Participants are examined on average every 6 months. Brain donation was available to all interested consenting participants. Neuropathology was assessed using the National Alzheimer’s Coordinating Center Neuropathology form v. 10.ResultAs of January 2022, 216 participants (26% of sample) were enrolled in autopsy (autopsy enrollees: 20% Asian, 15% African American, 17% Latino, 9% Multiracial/Other, and 39% NHW) with 25 deceased and neuropathological evaluations completed. Average age of death was 95 years (range 91‐106), 13 (62.5%) were female, 6 Latino, 14 NHW, 3 Multiracial, 1 Asian, and 1 African American. At final clinical exam, 3 participants had dementia (12%), 8 questionable/mild cognitive impairment (32%), and 14 were cognitively normal (56%). With respect to Alzheimer’s disease (AD) neuropathologic diagnosis, 8 met criteria for intermediate likelihood (32%), 11 low (44%), and 6 did not have AD (24%); none had high AD likelihood. All participants had some level of neurofibrillary tangles (NFTs); median Braak NFT stage was II (range I‐V). Six participants lacked plaques, and highest Thal phase was 4. Eleven participants (44%) had Lewy bodies. Hippocampal sclerosis was seen in 1 participant, whereas TDP‐43 inclusions were detected in 5 (20%). Cerebral amyloid angiopathy was seen in 13 participants (25%). The most common assessed pathologies were age related tau astrogliopathy in 19 participants (76%) and some degree of arteriolosclerosis in 24 participants (96%) although only 4 were considered to have severe arteriolosclerosis.ConclusionThis diverse cohort of oldest‐old individuals indicate numerous brain pathologies are present with advanced age, albeit most participants having mild severity and distributions of pathologies providing further evidence of the complex and multifactorial nature of clinic‐pathological correlations.

Characterization of tau PET according to amyloid chronicity

AbstractBackgroundThis work examined tau PET (MK‐6240 SUVR) relative to amyloid chronicity (duration of amyloid positivity (A+)) to better understand neurofibrillary tangle (NFT) spatial burden across the time course of Alzheimer’s disease (AD).MethodIndividuals (N=457, 68.3±7.1 years, 417 CU, 30 MCI, 10 dementia) from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin AD Research Center underwent amyloid and tau PET and neuropsychological assessment. Cortical 11C‐PiB DVR and sampled iterative local approximation was used to estimate A+ onset age and years of A+ duration at tau PET. Tau burden was quantified using 18F‐MK‐6240 SUVR (70‐90 min, inferior cerebellar GM reference region). MK‐6240 SUVR was assessed for relationships with A+ duration (continuous and grouped by decade) and clinical diagnosis as well as spatial patterns corresponding to Braak NFT stages. Regional and voxelwise analyses were performed.ResultMK‐6240 SUVR was positively associated with A+ duration in regions associated with Braak NFT stages I‐VI while age was not associated after accounting for A+ duration (Figure 1A). In the CU subset, the MK‐6240/A+ duration association was spatially restricted to regions associated with NFT stages I‐IV(Figure 1B). Voxelwise MK‐6240 analyses revealed that with each decade of A+ duration, the spatial extent of measurable tau “spread”(ie .progressed) from regions associated with early to late Braak NFT stages (Figure 2A). Similar patterns were observed in the CU subset, but with lower SUVR and signal spatially restricted to the medial temporal lobe (MTL; Figure 2B). Regional analyses of MK‐6240 SUVR Z‐scores indicated significant stepwise increases across A+ duration groups (A‐ &lt; A+ 0‐10 years &lt; A+ 10‐20 years &lt;A+ 20+ years; Figure 3A) and across clinical groups (CN A‐ &lt; CN A+ &lt; MCI A+ &lt; AD A+; Figures 3B). Between group differences were largest in the entorhinal cortex and MTL Meta‐ROI for both A+ duration and clinical diagnosis groups (Figure 4A‐B).ConclusionResults suggest that entorhinal and MTL regions were most sensitive to early amyloid pathology and cognitive changes in AD. Applying the amyloid chronicity framework to tau PET data enables 'pseudo'spatiotemporal characterization of tau deposition patterns in the AD continuum. Longitudinal assessment of spatiotemporal tau deposition patterns is ongoing.

TAR DNA‐binding protein 43 (TDP‐43) contributes to the mismatch between medial temporal volumes and flortaucipir uptake in elderly patients with Alzheimer’s disease neuropathologic changes

AbstractBackgroundWe previously demonstrated that Alzheimer’s disease (AD) patients ≥70 y/o tend to have smaller medial temporal volumes in the presence of relatively less medial temporal 18F‐flortaucipir‐PET uptake compared to young AD patients. TAR DNA‐binding protein 43 (TDP‐43) is frequently found in the brains of AD patients and is associated with old age and medial temporal atrophy. In this study, we aimed to determine whether TDP‐43 could be contributing to the mismatch between medial temporal volumes and flortaucipir‐PET uptake in older AD patients.MethodWe identified 77 participants (median age at death 79 years [range: 51‐99]) who had been enrolled into the Mayo Clinic Alzheimer’s Disease Research Center or Neurodegenerative Research Group (NRG), had undergone flortaucipir‐PET and volumetric MRI scans close to death, and autopsy confirmed AD neuropathological changes, as well as TDP‐43 assessments. Grey matter volumes and flortaucipir standard uptake value ratios (SUVRs) were calculated for hippocampus, amygdala, entorhinal, inferior temporal, and midfrontal cortices. We used bivariate‐response linear regression modelling, adjusting for Braak neurofibrillary tangle stage, to estimate the effect of TDP‐43 and age on gray matter volume and flortaucipir uptake, and tested whether TDP‐43 effect sizes varied according to age.ResultAfter accounting for Braak stage, older individuals tended to have significantly lower flortaucipir uptake across regions and lower hippocampal and entorhinal cortex (ERC) volumes. TDP‐43 was associated with reduced hippocampus and ERC volumes but was unrelated to flortaucipir SUVRs (Figure 1). Notably, the TDP‐43 effect size for the hippocampus and ERC was largely consistent across age, i.e., at any age, TDP‐43‐positive participants had significantly smaller hippocampal (∼12% decrease) and ERC (13% decrease) volumes than TDP‐43‐negative participants. However, at older ages, the mean volumes in the whole cohort and, more evidently, in those with dementia moved closer towards the mean of those with TDP‐43 (Figure 1), likely attributable to the increasing frequency of TDP‐43 with age.ConclusionTDP‐43 is a major contributor to the mismatch between flortaucipir uptake and medial temporal lobe volumes in older AD patients where lower medial temporal regional volumes are observed in the presence of less flortaucipir uptake.

Plasma Biomarkers of Amyloid and Neurodegeneration predictive of Neuropathologic Scales of Cerebrovascular Disease

AbstractBackgroundBlood‐based biomarkers of amyloid and neurodegeneration are increasingly used in clinical trials and entering clinical use. Differentially mapping the plasma markers to post‐mortem neuropathology in a community‐based sample is critical for interpretation.MethodWe identified 64 Mayo Clinic Study of Aging (MCSA) participants with antemortem plasma markers (Aβ42, Aβ40, NfL, T‐tau, Aβ42/40 ratio) measured on the Quanterix Simoa HD‐1 analyzer and with postmortem neuropathologic assessments of Alzheimer’s pathology (Braak tangle stage, Thal phase, neuritic plaque burden) and cerebrovascular pathology (Strozyk scale focused on macrovascular brain changes and Kalaria scale focused on detailed micro‐ and macro‐ vascular brain changes). Weighted linear regression models with adjustment for time between plasma markers and death were conducted with exact permutation tests to evaluate the relationships between antemortem plasma and postmortem neuropathology markers.ResultHigher plasma NfL levels and Aβ42/40 ratio were associated with both cerebrovascular neuropathologic scales (p&lt;0.05) but were not associated with Braak neurofibrillary tangle stage, neuritic plaque score, or Thal stage (p&gt;0.5). Plasma T‐tau was not associated with any pathological assessment. Plasma Aβ42/40 and NfL explained up to 18% of the variability in cerebrovascular neuropathologic scales.ConclusionIn this community sample of participants predominantly without dementia, plasma markers for amyloid (Aβ42/40) and neurodegeneration (NfL) were associated with cerebrovascular neuropathology at autopsy. NfL is a non‐specific marker of brain injury, therefore, its association with cerebrovascular neuropathology was in the expected direction. The association between greater cerebrovascular neuropathology and elevated Aβ42/40 requires further investigation. These findings provide evidence that cerebrovascular disease may significantly influence levels of plasma biomarkers proposed for Alzheimer’s disease. This information will be important to consider for accurate clinical interpretation of the proposed biomarkers.

Diverse limbic comorbidities cause limbic and temporal atrophy in lewy body disease

BackgroundIn contrast to Alzheimer's disease (AD)-related pathology, the influence of comorbid limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) or argyrophilic grains (AG) on structural imaging in Lewy body disease (LBD) has seldom been evaluated. ObjectiveThis study aimed to investigate whether non-AD limbic comorbidities, including LATE-NC and AG, cause cortical atrophy in LBD. MethodsSeventeen patients with pathologically confirmed LBD with lower Braak neurofibrillary tangle stage (<IV) and 10 healthy controls (HC) were included. Based on the presence of comorbid LATE-NC or AG, LBD patients were subdivided into nine patients with these proteinopathies (mixed LBD [mLBD]) and eight without (pure LBD [pLBD]). In addition to clinical feature evaluation, gray matter atrophy on voxel-based morphometry was compared between the two LBD and HC groups. ResultsThe mean age at antemortem magnetic resonance imaging of the mLBD patients was higher than that of the pLBD patients (84.3 ± 3.9 vs. 76.5 ± 10.5; p = .046). Irrespective of the presence or absence of comorbid LATE-NC or AG, all patients were clinically diagnosed with probable dementia with Lewy bodies or Parkinson's disease with dementia, respectively. Compared to the pLBD group, the mLBD group showed more conspicuous cortical atrophy of the bilateral hippocampus, amygdala, and temporal pole. ConclusionsNon-AD limbic comorbidities, including LATE-NC and AG, are associated with limbic and temporal atrophy in older patients with LBD. Therefore, the possibility of non-AD limbic comorbidities should be considered in the diagnosis of elderly patients with dementia with clinical symptoms of LBD and medial temporal atrophy.

Longitudinal Patterns of Cortical Atrophy on MRI in Patients With Alzheimer Disease With and Without Lewy Body Pathology.

Although Alzheimer disease (AD) and dementia with Lewy bodies (DLBs) represent 2 different pathologies, they have clinical overlap, and there is a significant degree of co-occurrence of their neuropathologic findings. Many studies have examined imaging characteristics in clinically diagnosed patients; however, there is a relative lack of longitudinal studies that have studied patients with pathologic confirmation. We examined whether there were differences in longitudinal patterns of cortical atrophy between patients with both AD and DLB (AD/DLB) vs those with AD alone. We collected and analyzed clinical and neuroimaging data from the AD Neuroimaging Initiative (ADNI) database for patients who underwent autopsy. The rates of change in various neuropsychological assessments were not significantly different between patients with AD/DLB and AD, and each group had neuropsychological outcomes consistent with disease progression. For our neuroimaging analysis, we used a linear mixed-effects model to examine whether there were longitudinal differences in cortical rates of atrophy between patients with AD/DLB and AD. Autopsies and serial neuroimaging were available on 48 patients (24 AD and 24 AD/DLB). Patients with AD alone had significantly higher atrophy rates in the left cuneus, lateral occipital, and parahippocampal regions over time when compared with patients with concomitant DLB, after covarying for interval from imaging to autopsy, sex, and total estimated intracranial volume. Site ID was included as a random effect to account for site differences. For these regions, the rate of decline over time in the AD/DLB group was less steep by a difference of 0.1887, 0.395, and 0.0989, respectively (p = 0.022, 0.006, and 0.006). The lattermost left cuneus volume measurement and Braak Lewy score had a Pearson product-moment correlation of 0.37, p = 0.009, while the lattermost left parahippocampal volume measurement and Braak neurofibrillary tangle score had a Pearson product-moment correlation of -0.327, p = 0.02. Patients with AD had more significant atrophy in the left cuneus, lateral occipital, and parahippocampal regions when compared with patients with AD/DLB. These regions are known to distinguish DLB and AD pathology cross-sectionally but here are shown to distinguish longitudinal disease progression.

LATE-NC aggravates GVD-mediated necroptosis in Alzheimer’s disease

It has become evident that Alzheimer’s Disease (AD) is not only linked to its hallmark lesions—amyloid plaques and neurofibrillary tangles (NFTs)—but also to other co-occurring pathologies. This may lead to synergistic effects of the respective cellular and molecular players, resulting in neuronal death. One of these co-pathologies is the accumulation of phosphorylated transactive-response DNA binding protein 43 (pTDP-43) as neuronal cytoplasmic inclusions, currently considered to represent limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), in up to 70% of symptomatic AD cases. Granulovacuolar degeneration (GVD) is another AD co-pathology, which also contains TDP-43 and other AD-related proteins. Recently, we found that all proteins required for necroptosis execution, a previously defined programmed form of neuronal cell death, are present in GVD, such as the phosphorylated necroptosis executioner mixed-lineage kinase domain-like protein (pMLKL). Accordingly, this protein is a reliable marker for GVD lesions, similar to other known GVD proteins. Importantly, it is not yet known whether the presence of LATE-NC in symptomatic AD cases is associated with necroptosis pathway activation, presumably contributing to neuron loss by cell death execution. In this study, we investigated the impact of LATE-NC on the severity of necroptosis-associated GVD lesions, phosphorylated tau (pTau) pathology and neuronal density. First, we used 230 human post-mortem cases, including 82 controls without AD neuropathological changes (non-ADNC), 81 non-demented cases with ADNC, i.e.: pathologically-defined preclinical AD (p-preAD) and 67 demented cases with ADNC. We found that Braak NFT stage and LATE-NC stage were good predictors for GVD expansion and neuronal loss in the hippocampal CA1 region. Further, we compared the impact of TDP-43 accumulation on hippocampal expression of pMLKL-positive GVD, pTau as well as on neuronal density in a subset of nine non-ADNC controls, ten symptomatic AD cases with (ADTDP+) and eight without LATE-NC (ADTDP−). Here, we observed increased levels of pMLKL-positive, GVD-exhibiting neurons in ADTDP+ cases, compared to ADTDP− and controls, which was accompanied by augmented pTau pathology. Neuronal loss in the CA1 region was increased in ADTDP+ compared to ADTDP− cases. These data suggest that co-morbid LATE-NC in AD impacts not only pTau pathology but also GVD-mediated necroptosis pathway activation, which results in an accelerated neuronal demise. This further highlights the cumulative and synergistic effects of comorbid pathologies leading to neuronal loss in AD. Accordingly, protection against necroptotic neuronal death appears to be a promising therapeutic option for AD and LATE.

Spatiotemporal characterization of cellular tau pathology in the human locus coeruleus–pericoerulear complex by three-dimensional imaging

Tau pathology of the noradrenergic locus coeruleus (LC) is a hallmark of several age-related neurodegenerative disorders, including Alzheimer’s disease. However, a comprehensive neuropathological examination of the LC is difficult due to its small size and rod-like shape. To investigate the LC cytoarchitecture and tau cytoskeletal pathology in relation to possible propagation patterns of disease-associated tau in an unprecedented large-scale three-dimensional view, we utilized volume immunostaining and optical clearing technology combined with light sheet fluorescence microscopy. We examined AT8+ pathological tau in the LC/pericoerulear region of 20 brains from Braak neurofibrillary tangle (NFT) stage 0–6. We demonstrate an intriguing morphological complexity and heterogeneity of AT8+ cellular structures in the LC, representing various intracellular stages of NFT maturation and their diverse transition forms. We describe novel morphologies of neuronal tau pathology such as AT8+ cells with fine filamentous somatic protrusions or with disintegrating soma. We show that gradual dendritic atrophy is the first morphological sign of the degeneration of tangle-bearing neurons, even preceding axonal lesions. Interestingly, irrespective of the Braak NFT stage, tau pathology is more advanced in the dorsal LC that preferentially projects to vulnerable forebrain regions in Alzheimer’s disease, like the hippocampus or neocortical areas, compared to the ventral LC projecting to the cerebellum and medulla. Moreover, already in the precortical Braak 0 stage, 3D analysis reveals clustering tendency and dendro-dendritic close appositions of AT8+ LC neurons, AT8+ long axons of NFT-bearing cells that join the ascending dorsal noradrenergic bundle after leaving the LC, as well as AT8+ processes of NFT-bearing LC neurons that target the 4th ventricle wall. Our study suggests that the unique cytoarchitecture, comprised of a densely packed and dendritically extensively interconnected neuronal network with long projections, makes the human LC to be an ideal anatomical template for early accumulation and trans-neuronal spreading of hyperphosphorylated tau.

Neuropathology of Dementia Disorders.

This article provides an overview of the neuropathology of common age-related dementing disorders, focusing on the pathologies that underlie Alzheimer disease (AD) and related dementias, including Lewy body dementias, frontotemporal dementia, vascular dementia, limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy (LATE), and mixed-etiology dementias. This article also discusses the underlying proteinopathies of neurodegenerative diseases (eg, amyloid-β, paired helical filament tau, α-synuclein, and TDP-43 pathology) and vascular pathologies, including tissue injury (eg, infarcts, hemorrhages) with or without vessel disease. New criteria for AD pathologic diagnosis highlight amyloid-β as the sine qua non of AD; they require molecular markers of amyloid and establish a minimum threshold of Braak neurofibrillary tangle stage 3. Pathologic diagnosis is separated from clinical disease (ie, pathologic diagnosis no longer requires dementia). TDP-43 pathology, a major pathology in a frontotemporal dementia subtype, was found as a central pathology in LATE, a newly named amnestic disorder. Multiple pathologies (often co-occurring with AD) contribute to dementia and add complexity to the clinical picture. Conversely, Lewy body, LATE, and vascular dementias often have accompanying AD pathology. Pathology and biomarker studies highlight subclinical pathologies in older people without cognitive impairment. This resilience to brain pathology is common and is known as cognitive reserve. The pathologies of dementia in aging are most commonly amyloid, tangles, Lewy bodies, TDP-43, hippocampal sclerosis, and vascular pathologies. These pathologies often co-occur (mixed pathologies), which may make specific clinical diagnoses difficult. In addition, dementia-related pathologies are often subclinical, suggesting varying levels of resilience in older people.

Tau polygenic risk scoring: a cost-effective aid for prognostic counseling in Alzheimer's disease.

Tau deposition is one of two hallmark features of biologically defined Alzheimer's disease (AD) and is more closely related to cognitive decline than amyloidosis. Further, not all amyloid-positive individuals develop tauopathy, resulting in wide heterogeneity in clinical outcomes across the population with AD. We hypothesized that a polygenic risk score (PRS) based on tau PET (tau PRS) would capture the aggregate inherited susceptibility/resistance architecture influencing tau accumulation, beyond solely the measurement of amyloid-β burden. Leveraging rich multimodal data from a population-based sample of older adults, we found that this novel tau PRS was a strong surrogate of tau PET deposition and captured a significant proportion of the variance in tau PET levels as compared with amyloid PET burden, APOE (apolipoprotein E) ε4 (the most common risk allele for AD), and a non-APOE PRS of clinical case-control AD risk variants. In independent validation samples, the tau PRS was associated with cerebrospinal fluid phosphorylated tau levels in one cohort and with postmortem Braak neurofibrillary tangle stage in another. We also observed an association of the tau PRS with longitudinal cognitive trajectories, including a statistical interaction of the tau PRS with amyloid burden on cognitive decline. Although additional study is warranted, these findings demonstrate the potential utility of a tau PRS for capturing the collective genetic background influencing tau deposition in the general population. In the future, a tau PRS could be leveraged for cost-effective screening and risk stratification to guide trial enrollment and clinical interventions in AD.

Limbic-Predominant Age-Related TDP-43 Encephalopathy: Medical and Pathologic Factors Associated With Comorbid Hippocampal Sclerosis.

Limbic-predominant age-related Tar DNA binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) is present in ≈25% of older persons' brains and is strongly associated with cognitive impairment. Hippocampal sclerosis (HS) pathology is often comorbid with LATE-NC, but the clinical and pathologic correlates of HS in LATE-NC are not well understood. This retrospective autopsy cohort study used data derived from the National Alzheimer's Coordinating Center Neuropathology Data Set, which included neurologic status, medical histories, and neuropathologic results. All autopsies were performed in 2014 or later. Among participants with LATE-NC, those who also had HS pathology were compared with those without HS with regard to candidate risk factors or common underlying diseases. Statistical significance was set at nominal p < 0.05 in this exploratory study. A total of 408 participants were included (n = 221 were LATE-NC+/HS-, n = 145 were LATE-NC+/HS+, and n = 42 were LATE-NC-/HS+). Most of the included LATE-NC+ participants were severely impaired cognitively (83.3% with dementia). Compared to HS- participants, LATE-NC+ participants with HS trended toward having worse cognitive status and scored lower on the Personal Care and Orientation domains (both p = 0.03). Among LATE-NC+ participants with Braak neurofibrillary tangle (NFT) stages 0 to IV (n = 88), HS+ participants were more impaired in the Memory and Orientation domains (both p = 0.02). There were no differences (HS+ compared with HS-) in the proportion with clinical histories of seizures, stroke, cardiac bypass procedures, diabetes, or hypertension. The HS+ group lacking TDP-43 proteinopathy (n = 42) was relatively likely to have had strokes (p = 0.03). When LATE-NC+ participants with or without HS were compared, there were no differences in Alzheimer disease neuropathologies (Thal β-amyloid phases or Braak NFT stages) or Lewy body pathologies. However, the HS+ group was less likely to have amygdala-restricted TDP-43 proteinopathy (LATE-NC stage 1) and more likely to have neocortical TDP-43 proteinopathy (LATE-NC stage 3) (p < 0.001). LATE-NC+ brains with HS also tended to have more severe circle of Willis atherosclerosis and arteriolosclerosis pathologies. In this cohort skewed toward participants with severe dementia, LATE-NC+ HS pathology was not associated with seizures or with Alzheimer-type pathologies. Rather, the presence of comorbid HS pathology was associated with more widespread TDP-43 proteinopathy and with more severe non-β-amyloid vessel wall pathologies.

Patterns of Distribution of 18F-THK5351 Positron Emission Tomography in Alzheimer's Disease Continuum.

Alzheimer's disease (AD) is conceptualized as a biological continuum encompassing the preclinical (clinically asymptomatic but with evidence of AD pathology) and clinical (symptomatic) phases. Using 18F-THK5351 as a tracer that binds to both tau and monoamine oxidase B (MAO-B), we investigated the changes in 18F-THK5351 accumulation patterns in AD continuum individuals with positive amyloid PET consisting of cognitively normal individuals (CNp), amnestic mild cognitive impairment (aMCI), and AD and cognitively normal individuals (CNn) with negative amyloid PET. We studied 69 individuals (32 CNn, 11 CNp, 9 aMCI, and 17 AD) with structural magnetic resonance imaging, 11C-Pittsburgh compound-B (PIB) and 18F-THK5351 PET, and neuropsychological assessment. 18F-THK5351 accumulation was evaluated with visual analysis, voxel-based analysis and combined region of interest (ROI)-based analysis corresponding to Braak neurofibrillary tangle stage. On visual analysis, 18F-THK5351 accumulation was increased with stage progression in the AD continuum. On voxel-based analysis, there was no statistical difference in 18F-THK5351 accumulation between CNp and CNn. However, a slight increase of the bilateral posterior cingulate gyrus in aMCI and definite increase of the bilateral parietal temporal association area and posterior cingulate gyrus/precuneus in AD were detected compared with CNn. On ROI-based analyses, 18F-THK5351 accumulation correlated positively with supratentorial 11C-PIB accumulation and negatively with the hippocampal volume and neuropsychological assessment. The AD continuum showed an increase in 18F-THK5351 with stage progression, suggesting that 18F-THK5351 has the potential to visualize the severity of tau deposition and neurodegeneration in accordance with the AD continuum.